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Biological membranes are bilipid layers. In a real cell the membrane phospholipids create a spherical three dimensional lipid bilayer shell around the cell. However, they are often represented two-dimensionally as:

The circle, or head, is the negatively charged phosphate group and the two tails are the two highly hydrophobic hydrocarbon chains of the phospholipid. The tails of the phospholipids orient towards each other creating a hydrophobic environment within the membrane. This leaves the charged phosphate groups facing out into the hydrophilic environment. The membrane is approximately 5 nm thick.

This bilipid layer is semipermeable, meaning that some molecules are allowed to pass freely (diffuse) through the membrane.

The lipid bilayer is virtually impermeable to large molecules, relatively impermeable to molecules as small as charged ions.

It is quite permeable to lipid soluble low molecular weight molecules. It is substantially permeable to water molecules. Molecules that can diffuse through the membrane due so at differing rates depending upon their ability to enter the hydrophobic interior of the membrane bilayer.

From left to right are (a) a protein whose polypeptide chain traverses the membrane once as an a helix, (b) a protein that forms several transmembrane  helices connected by hydrophilic loop regions, (c) a protein with several b strands that form a channel through the membrane, and (d) a protein that is anchored to the membrane by one a helix parallel to the plane of the membrane.

An electron density map to 7 Å resolution (a) was obtained and interpreted in terms of seven transmembrane helices (b). In 1990, the resolution was extended to 3 Å, which confirmed the presence of the seven  helices connected by loop regions and where the retinal molecule was bound to bacteriorhodopsin.

The light-absorbing pigment retinal undergoes a conformational change called isomerization when it absorbs light. One part of the molecule rotates 180° around a double bond between two carbon atoms (green). The geometry of the molecule is changed by this rotation from a trans form to a cis form.

Protons are pumped from cytosol to the extracellular space, creating a proton gradient.

The generated proton gradient is used to produce ATP and to transport ions and molecules across the membrane.

The protein adopts two main conformational states, tense (T) and relaxed (R). The T state binds trans-retinal tightly and the R state binds cis-retinal. The structure of bacteriorhodopsin in the T state, shown in (a), with trans-retinal bound to Lys 216 via a Schiff base. A proton is transferred from the Schiff base to Asp 85 following isomerization of retinal and a conformational change of the protein, as shown in (b).

The structure of bacteriorhodopsin in the R state with cis-retinal bound (c). A proton is transferred from Asp-96 to the Schiff base and from Asp-85 to the extracellular space. A proton is transferred from the cytoplasm to Asp-96, as shown in (d).

Ribbon diagram of one subunit of porin from Rhodobacter capsulatus viewed from within the plane of the membrane. Sixteen b strands form an antiparallel b barrel that traverses the membrane. The long loop between b strands 5 and 6 (red) (eyelet) constricts the channel of the barrel. Two calcium atoms are shown as orange circles.

Schematic diagram for the structure of a potassium channel viewed perpendicular to the plane of the membrane. The molecule is tetrameric with a hole in the middle that forms the ion pore (purple). Each subunit forms two transmembrane helices, the inner and the outer helix. The pore helix and loop regions build up the ion pore in combination with the inner helix.

Diagram showing two subunits of the K+ channel, illustrating the way the selectivity filter is formed. Main-chain atoms line the walls of this narrow passage with carbonyl oxygen atoms pointing into the pore, forming binding sites for K+ ions.

The cytosolic side of the pore begins as a water-filled channel that opens up into a water-filled cavity near the middle of the membrane. A narrow passage, the selectivity filter, links this cavity to the external solution. Three potassium ions (purple spheres) bind in the pore. The pore helices (red) are oriented such that their carboxyl end (with a negative dipole moment) is oriented towards the center of the cavity to provide a compensating dipole charge to the K+ ions.

The three-dimensional structure of a photosynthetic reaction center of a purple bacterium was the first high-resolution structure to be obtained for a membrane-bound protein. The molecule contains four subunits: L, M, H, and a cytochrome. Subunits L and M bind the photosynthetic pigments, and the cytochrome binds four heme groups. The L (yellow) and the M (red) subunits each have five trans-membrane -helices A-E. The H subunit (green) has one such trans-membrane helix, AH, and the cytochrome (blue) has none. Approximate membrane boundaries are shown. The photosynthetic pigments and the heme groups appear in black.

All the steps in the transport of glucose into cells are freely reversible, the direction of movement of glucose being dictated by the relative concentrations of glucose on either side of membrane. In order to maintain the concentration gradient across the membrane, the glucose is rapidly phosphorylated inside the cell to glucose 6-phosphate by hexokinase.

Collagens are proteins that assemble into fibrous super-molecular aggregates in the extracellular space, which comprise three polypeptide chains with a large number of repeat sequences Gly-X-Y where X is often proline and Y is often hydroxyproline.

Hydroxyproline is formed by the post-translational modification of proline by prolyl hydroxylase.

Each polypeptide chain in the collagen molecule folds into an extended polyproline type II helix with a rise per turn along the helix of 9.6 Å comprising 3.3 residues. In the collagen molecule, three such chains are supercoiled about a common axis to form a 3000-Å-long rod-like molecule. The amino acid sequence contains repeats of -Gly-X-Y- where X is often proline and Y is often hydroxyproline.

Models of a collagen-like peptide with a mutation Gly to Ala in the middle of the peptide (orange).

Each polypeptide chain is folded into a polyproline type II helix and three chains form a superhelix similar to part of the collagen molecule. The alanine side chain is accommodated inside the superhelix causing a slight change in the twist of the individual chains

Space-filling models of intrachain water bridges observed in the crystal structure of a collagen-like peptide. The oxygen atoms of the water molecules are yellow and the hydrogen atoms are white. A bridge of three water molecules hydrogen bonded to two C=O groups and linked to other water molecules are shown in (a). Long bridges of water molecules establish a network that surrounds the triple helix shown in (b).

The domain organization of intermediate filament protein monomers. Most intermediate filament proteins share a similar rod domain that is usually about 310 amino acids long and forms an extended  helix. The amino-terminal and carboxy-terminal domains are non-a-helical and vary greatly in size and sequence in different intermediate filaments.

The monomer shown in (a) pairs with an identical monomer to form a coiled-coil dimer (b). The dimers then line up to form an antiparallel tetramer (c). Within each tetramer the dimers are staggered with respect to one another, allowing it to associate with another tetramer (d). In the final 10-nm rope-like intermediate filament, tetramers are packed together in a helical array (e).

Schematic diagram of the myosin molecule, comprising two heavy chains (green) that form a coiled-coil tail with two globular heads and four light chains (gray) of two slightly differing sizes, each one bound to each heavy-chain globular head.

Spider fibers are composite materials formed by large silk fibroin polypeptide chains with repetitive sequences that form  sheets. Some regions of the chains participate in forming 100 nm crystals, while other regions are part of a less-ordered mesh-work in which the crystals are embedded. The diagram shows a model of the current concepts of how these fibers are built up, which probably will be modified and extended as new knowledge is gained.

Alzheimer's disease is characterized by the deposition of insoluble amyloid fibrils as amyloid plaques in the neurophil as well as the accumulation of neurofibrillary tangles in cell bodies of neurons.

The amyloid fibrils are composed of the amyloid b peptide (Ab), a 39-43 amino acid residue peptide produced by cleavage from a larger amyloid precursor protein, APP. The Ab peptide is known to be present in unaffected individuals and is thought to have a normal physiological role. However, in Alzheimer's disease patients, the A peptide forms ordered aggregates which are deposited extracellularly as amyloid plaques or senile plaques in the neurophil, and as vascular deposits.

Alzheimer's disease is not the only disease in which amyloid fibrils are involved in the pathology. There is now a list of some 16 proteins which can form amyloid fibrils in various diseases. These proteins vary considerably in their primary structure, function, size and tertiary structure, and yet they appear to form amyloid fibrils, which show very few structural differences.

Electron microscopy has shown that amyloid fibrils are straight, un-branching fibers of 70-120 Å in diameter and of indeterminate length. All amyloid fibrils stain with the dye Congo red and give a green birefringence when examined under cross-polarized light, and finally they reveal a cross-β fiber diffraction pattern which suggests aβ-sheet type structure for the fibrils.

A strong 4.8 Å reflection on the meridian corresponds to the hydrogen bonding distance between β-strands (shown on the right), and a more diffuse 10 - 11 Å reflection on the equator shows the inter-sheet distance of about 10.7 Å. A spacing of 9.6 Å would correspond to the repeat distance for an anti-parallel arrangement of β-strands.

Structural studies of amyloid fibrils from Alzheimer's disease brain have proved extremely difficult due to the insolubility of the plaques. Examination of the structure of amyloid fibrils has concentrated on fibrils formed in vitro from synthetic peptides homologous to the Aβ peptide.

However, synthetic amyloid fibrils are problematic to study using conventional structural techniques. Methods such as single crystal X-ray crystallography and solution nuclear magnetic resonance (NMR) cannot be used on fibrils since they are insoluble.

Structure prediction studies have indicated that the last 10 residues at the C-terminal and residues 17 - 21 of Aβ show the greatest hydrophobicity, while the C-terminus (from residue 28) showed a high probability for β-sheet structure. Residues 9 - 21showed a lower probability for β-sheet. Two β-turns are predicted between residues 6 and 8, and residues 23 and 27.

The structure of the Aβ peptide has been extensively studied in solution, although it is necessary to use organic solvents such as DMSO and TFE, and detergents such as SDS to keep Aβ soluble.

NMR, CD and FTIR studies have shown that Aβ generally forms a-helical conformation in organic solvents, whereas in aqueous buffers or in water it is predominantly β-sheet, although this can be affected by pH, concentration and incubation time.

A b-sheet content is linked to insolubility and related to neurotoxicity. The fibrillar state is associated with protease resistance. The A b peptide undergoes a conformation switch from a-helical to b-sheet structure during amyloidogenesis.

The N-terminus is thought to be important for initiating conformational switching. Introduction of a single amino acid substitution (V18A) in Ab1-40, which leads to an increased propensity for a-helical conformation compared to wild type, was found to be related to a decreased ability to form amyloid fibrils. Substitution of residues Lys16 in Ab1-28 or Phe19 or 20 for Ala in 10 - 23 results in peptides unable to form amyloid-like fibrils

A short peptide 14 - 23 is capable of forming amyloid fibrils in vitro and the region 11 - 24 is thought to play an important role in the conversion.

Residues 25 - 35 have been implicated in neurotoxicity, and residues 34 - 42 are very hydrophobic and are thought to be situated in the transmembrane region in APP. Peptides of this region are extremely insoluble and have been implicated in nucleating amyloid fibril formation.

It is thought that fibril formation proceeds via a nucleation dependent mechanism, which is highly concentration dependent and proceeds via a partially folded intermediate.

Purification of Ab1-42 peptide from the brain of an Alzheimer's disease patient yielded stable dimeric and trimeric forms, and monomers that were capable of forming fibrils in vitro

Studies of the short Ab14-23 peptide suggest that fibril polymerization proceeds via the formation of dimers, then tetramers and finally oligomers, in which the charged residues form ion pairs and the hydrophobic residues form a hydrophobic core.

Shown to the left is the hierarchy of structure from the Ab peptide folded into a b-pleated sheet structure through protofilaments to amyloid fibrils with b-strands running perpendicular to the fiber axis and held together by hydrogen bonding.